Cleft lip and cleft palate can serve as a sentinel for birth defects in general for the impact that they have on fetal and maternal health. As sentinels, they are easy to identify and require a high input of surgical and medical care, but also commonly result in long-term survival of affected individuals, even when untreated. They are common with the average frequency of about 1:1000 in most South American countries. Their etiology is complex, although it is clear that genes and genetic and environment interactions play an important role. Nutritional factors in clefts are well recognized and have been studied for over 40 years. Recent evidence that folate or B6 deficiency, as well as a role for smoking and alcohol use, suggest that environmental interventions in the form of supplementation or preventive strategies may be effective in decreasing the frequency of these birth defects. The South American birth defects registry, Estudio Collaborativo Latinoamericano de Malformaciones Congenitas (ECLAMC), has for many years provided epidemiologic information on the frequency of birth defects throughout South America. At the present time, folate supplementation has been introduced to one country in South America (Chile) and it is now possible to measure changes in outcomes of this based around the known preventive effect of folic acid supplementation for neural tube defects and the likely effect that it may have on cleft lip and cleft palate. Extensive populations of affected individuals such as those followed by the Centrinho clinic in Bauru provide high risk populations in which targeted interventions can be effectively studied. In this proposal, the applicants will use cleft lip and cleft palate as a sentinel defect to study the impact of birth defects in general on maternal, fetal and neonatal health and to carry out direct interventions on decreasing the number of these birth defects using both behavioral and medical interventions. The specific aims will include measuring the impact of the interventional use of folic acid supplementation on cleft lip and cleft palate and neural tube defects, measuring the impact of having a child born with a cleft on subsequent maternal, infant and family health, and finally, interventions to decrease the number of birth defects through the direct prevention strategies of smoking intervention and vitamin supplementation. The outcome of this project will be to further strengthen collaborative relationships in the area of craniofacial anomalies between Brazil and the US, to better understand the effects of birth defects and craniofacial anomalies in particular on maternal family units and to decrease the burden of these defects directly.